Intravenous Valproic Acid Research Articles

Population Pharmacokinetics and Loading Dose Optimization of Intravenous Valproic Acid in Hospitalized Thai Patients.

Our goal is to create a population pharmacokinetic (PK) model and identify the best loading dose (LD) of intravenous valproic acid for hospitalized Thai patients. Data from patients who received intravenous valproic acid and underwent measurement of serum valproic acid concentrations during hospitalization were collected retrospectively. A nonlinear mixed-effects modeling approach was conducted to estimate the PK parameters of valproic acid. Covariates affecting the PK parameters of valproic acid were examined and ranked based on their impact on the model's performance. Monte Carlo simulations of 1000 patients were conducted to estimate the optimal LD of valproic acid. A total of 120 hospitalized patients (51.7% male) with 167 valproic acid concentrations were included in the study. A linear one-compartment model with constant residual error was the best base model. An age-covariate model was the best predictor of valproic acid clearance (CL). The typical values of CL and volume of distribution for valproic acid were 0.77 L/h and 14.56 L, respectively. The LD of 1000-1200 mg intravenous was identified as the pragmatic option as an empirical regimen for hospitalized Thai patients. The recommended time to initiate maintenance dose (MD) is 4-8 h following the LD. The population PK model and optimal LD of valproic acid in hospitalized Thai patients has been established, and it may be advisable to initiate the MD at a later time for the elderly.

(149) Use of Intravenous Valproic Acid Loading in the Emergency Department for Acute Mania: Case Report and Literature Review

(149) Use of Intravenous Valproic Acid Loading in the Emergency Department for Acute Mania: Case Report and Literature Review

Valproate-related hyperammonemic encephalopathy with generalized suppression EEG: a case report.

Valproic acid (VPA) is a prevalent antiseizure medication (ASM) used to treat epilepsy. Valproate-related hyperammonemic encephalopathy (VHE) is a type of encephalopathy that can occur during neurocritical situations. In VHE, the electroencephalogram (EEG) displays diffuse slow waves or periodic waves, and there is no generalized suppression pattern. We present a case of a 29-year-old female with a history of epilepsy who was admitted for convulsive status epilepticus (CSE), which was controlled by intravenous VPA, as well as oral VPA and phenytoin. The patient did not experience further convulsions but instead developed impaired consciousness. Continuous EEG monitoring revealed a generalized suppression pattern, and the patient was unresponsive. The patient's blood ammonia level was significantly elevated at 386.8μmol/L, indicating VHE. Additionally, the patient's serum VPA level was 58.37μg/ml (normal range: 50-100μg/ml). After stopping VPA and phenytoin and transitioning to oxcarbazepine for anti-seizure and symptomatic treatment, the patient's EEG gradually returned to normal, and her consciousness was fully restored. VHE can cause the EEG to display a generalized suppression pattern. It is crucial to recognize this specific situation and not to infer a poor prognosis based on this EEG pattern.

Does diabetes mellitus affect the safety profile of valproic acid for the treatment of status epilepticus? A retrospective cohort study

BackgroundIn the treatment of status epilepticus less is known about the influence of comorbidities on the safety profile of anticonvulsive drugs. Especially patients with diabetes mellitus may be predisposed to certain adverse events that have been related to therapy with valproic acid. In this single-center retrospective cohort study we examined if the complications of the intravenous treatment with valproic acid is different in patients with or without diabetes.MethodsPatients who were treated for status epilepticus with intravenous valproic acid between 2008 and 2020 were identified. Primary endpoint was the discontinuation of therapy with valproic acid due to adverse events. Relevant secondary endpoints were the functional status at the time of discharge from hospital in comparison to the premorbid state and the in-hospital mortality. Both groups (patients with or without diabetes) were compared by Mann–Whitney U-Test or Pearson´s Chi2 test. To identify therapy with valproic acid as a risk factor of in-hospital mortality, a binary regression model was used.ResultsDuring the study period 408 patients and 482 episodes of status epilepticus were treated with intravenous valproic acid. Group comparisons did not reveal a significant difference in the rates of discontinuation of therapy. A difference was found in the rate of thrombocytopenia (p = 0.015), which occurred more often in patients with diabetes. In total, 36 hypoglycemic episodes could be identified, two occurred spontaneously under intravenous valproic acid. After correction for potential confounders, continuous therapy with valproic acid could not be confirmed as an independent risk factor for in-hospital mortality (p = 0.079). In patients with diabetes, the proportion of patients with a good functional state, indicated by the modified Rankin Scale, was significantly lower in both times (premorbid: 55% vs. 69%, p = 0.008; at discharge: 22% vs. 36%, p = 0.004).ConclusionsTolerability of the treatment with valproic acid was similar in patients with or without diabetes. Diabetes as a relevant comorbidity can signal a potentially increased risk of a poor outcome after status epilepticus.Trial registration: The study was registered at the German Clinical Trials Register on 8 April 2022 (DRKS 00,027,836).

Efficacy of Intravenous Valproic Acid and Oral Valproic Acid Tapers for Treatment of Pediatric Headaches in the Emergency Department (P15-2.001)

Efficacy of Intravenous Valproic Acid and Oral Valproic Acid Tapers for Treatment of Pediatric Headaches in the Emergency Department (P15-2.001)

Intravenous valproic acid for the treatment of inpatients with bipolar disorder experiencing manic or depressive episodes with mixed features

Intravenous valproic acid for the treatment of inpatients with bipolar disorder experiencing manic or depressive episodes with mixed features

Valproic Acid Administration in Management of Status Epilepticus Causing Reye’s Syndrome

AbstractIntroduction Valproic acid is commonly used to treat seizures in children. Regular use of valproic acid is known to cause hepatic dysfunction, and in extremely rare cases, it is known to have caused Reye’s syndrome. There are very few reports of Reye’s syndrome caused by valproic acid use.Methods A 2-year asymptomatic girl underwent modified Blalock–Taussig shunt surgery for correction of tetralogy of Fallot. Postoperatively the girl developed status epilepticus, which did not subside with initial use of intravenous midazolam and phenytoin sodium. She eventually responded to two doses of intravenous valproic acid administered 10 minutes apart. She developed depressed sensorium and was put on mechanical ventilation. The following day’s laboratory investigations revealed raised levels of serum ammonia, serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic-pyruvic transaminase (SGPT) with normal serum bilirubin. Thus, a diagnosis of Reye’s syndrome was established. The patient succumbed to disease 2 days later.Discussion Reye’s syndrome is a rare and a fulminant illness seen typically in children following a viral illness and/or use of salicylates or other medications. There are rare reports of Reye’s syndrome following use of medications like valproic acid. This patient had a noninflammatory encephalopathy with hepatic dysfunction following two doses of valproic acid.Conclusion There are very few reports on Reye’s syndrome in the literature as it is a rare condition and diagnosis is difficult. Knowledge of the presentation of Reye’s syndrome is essential for treatment and management. When using drugs like valproic acid in children, liver enzymes and serum ammonia levels should be monitored.

Is there evidence for using anticonvulsants in the prevention and/or treatment of delirium among older adults?

<h3>Introduction</h3> Delirium is an acute neuropsychiatric syndrome characterized by impaired attention, awareness and cognition. It develops over a short period of time (hours to days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day. The highest prevalence of delirium is found in the older adults, being particularly high in the hospitalized older adults. The highest incidence rates for delirium among the older adults are observed in the intensive care units, and in postoperative and palliative care settings. Delirium is associated with poorer clinical outcomes including a worsening of nutritional status, cognition and medical co-morbidities. It is associated with greater lengths and costs of hospitalization, and greater burden of care on the nursing staff. Delirium also increases the risk for developing cognitive impairment, institutionalization and death. The average medical care cost for individuals with delirium is more than two-and-a half times the cost for individuals without. Both non-pharmacologic and pharmacologic treatments are used in the management of delirium. Non-pharmacologic treatments that benefit older adults with delirium include frequent reorientation, making eye contact, frequent touching and using clear verbal instructions when talking to patients. Additionally, minimizing of sensory impairments including vision and hearing loss by use of assistive devices, reducing the use of physical restraints, providing treatment in a non-stimulating environment and minimizing staff and room changes, have proven beneficial as well. Pharmacotherapy is often used to treat the underlying causes of delirium in older adults, especially in the management of behaviors that are not managed by non-pharmacological strategies. Agents that have shown benefit among older adults with delirium include antipsychotics, cholinesterase inhibitors and benzodiazepines. Valproic acid derivatives have been used in the treatment of delirium among younger adults with some success. Many different mechanisms have been proposed for this, including the actions of valproic acid derivatives on the glutamatergic system, dopaminergic system, GABAergic system, Kynurenine Pathway. Oral or intravenous valproic acid preparations appear to be efficacious in delirium when antipsychotics and/or benzodiazepines are ineffective, the management requires large and/or frequent dosing of medications, or the medications cause significant adverse effects. Valproic acid derivatives have been beneficial in over 70% of the cases, with benefits noted in the first week of treatment, and the medication was well tolerated. Given the emerging evidence for the efficacy of valproic acid preparations among individuals with delirium, we decided to conduct a systematic review that examined the current evidence for using anticonvulsants in the prevention and/or treatment of delirium among older adults from published randomized control trials (RCTs). If there is good evidence for their use in the older adult population, then it would broaden the pharmaceutic options available to manage this serious condition among a vulnerable group of individuals. <h3>Methods</h3> A comprehensive search of databases: MEDLINE ALL (Ovid), Embase (Ovid), PsycINFO (Ovid), Web of Science Core Collection and Cochrane Central Register of Controlled was conducted. <h3>Results</h3> The search identified four RCTs that evaluated the use of anticonvulsants among older adults with delirium. One RCT evaluated the perioperative use of gabapentin among patients undergoing spinal surgery and the development of postoperative delirium. One RCT evaluated the relationship between the use of perioperative gabapentin and the development of postoperative delirium among patients undergoing spinal surgery and hip and knee arthroplasty. Two post-hoc analyses of RCTs that evaluated the use of gabapentin and pregabalin among patients undergoing total knee replacement (TKA) and total hip replacement (THA). The perioperative use of gabapentin reduced the incidence of postoperative delirium among older adults undergoing spinal surgery. The perioperative use of gabapentin did not reduce the rates, severity or duration of postoperative delirium among older adults who were undergoing spine and hip and knee arthroplasty. The perioperative use of gabapentin did not reduce the incidence or duration of postoperative delirium among older adults undergoing elective TKA. The perioperative use of pregabalin did not reduce the incidence of postoperative delirium among older adults undergoing elective THA. Gabapentin and pregabalin were well tolerated among the patients enrolled in these trials. There were no RCTs identified that evaluated the use of other anticonvulsants for the prevention and/or treatment of delirium among older adults. <h3>Conclusions</h3> Based on current evidence, the routine use of anticonvulsants for the prevention and/or treatment of delirium among older adults cannot be recommended.

Validation of intraosseous delivery of valproic acid in a swine model of polytrauma

BackgroundIntraosseous (IO) drug delivery may be necessary in emergency situations when intravenous access is unattainable. Valproic acid (VPA) is a histone deacetylase inhibitor that has previously been shown to improve...

Novel Pharmacological Approaches for Tourette Syndrome

The need to develop novel pharmacological approaches for TS is balanced by the necessity for interventions to be safe and tolerable. This review provides an overview of studies of medications for TS over the last 3 years. Four studies of deutetrabenazine and valbenazine in TS failed in their primary outcomes. Ecopipam was more effective than placebo in reducing tics in children. Preliminary evidence suggests that a new endocannabinoid modulator (ABX-1431) has an acute effect on tics in adults. Intravenous valproic acid was more effective than oral aripiprazole in children with severe tics. Taurine added to tiapride was superior to placebo added to tiapride in decreasing tics in children. The clonidine patch and vitamin D decreased tics in children compared with baseline assessment. Behavioral therapy was as effective as pharmacotherapy in decreasing tics in children. There is emerging evidence for new treatments for tics, but more methodologically rigorous studies are needed to inform practice recommendations.

Influence of valproate-induced hyperammonemia on treatment decision in an adult status epilepticus cohort

IntroductionStatus epilepticus (SE) is a neurological emergency in which immediate intervention is required to prevent permanent brain damage and death. Intravenous (IV) valproic acid (VPA) is often used for the treatment of SE. However, IV VPA frequently increases the blood ammonia level. In this study, we explore the impact of IV VPA-induced hyperammonemia (HA) on treatment management of SE and discuss the challenges related to this particular condition. MethodsWe used data from medical records of 31 adult patients (≥18 years) treated with IV VPA for SE at Oslo University Hospital between January 2006 and October 2019. Clinical and blood sample data and information about the influence of HA on treatment were collected. Correlations between ammonia levels and other continuous or categorical variables were tested using the Pearson's correlation coefficient. The Kruskal–Wallis H-test was used to analyze associations between different variables and treatment decisions. ResultsThirty of 31 patients had increased ammonia level during IV VPA treatment. In 16/30 patients, VPA was discontinued, and in 6/30 patients, the dose was reduced. We found a difference in the median peak ammonia level among the groups where VPA was discontinued (99 μmol/l), reduced (71 μmol/l), and continued (55.5 μmol/l) (P = 0.008). Also clinical status, measured by West Haven Criteria, varied among the groups where VPA was discontinued (3.5), reduced (2.5), and continued (2.0) (P = 0.01). Treatment decisions at peak ammonia were not associated with the level of liver enzymes and bilirubin. ConclusionHyperammonemia had a substantial impact on further management. To date, no recommendations exist on how to manage VPA-induced HA in SE. We call for systematic prospective studies and evidence-based guidelines.

Methods of An Open - Label Proof - of - Concept Trial of Intravenous Valproic Acid for Severe COVID-19

Introduction. Coronavirus disease 2019 (COVID-19) is the systemic entity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may cause death through severe atypical pneumonia and acute lung injury. Valproic acid (VPA) has shown anti-inflammatory activity and intrinsic antiviral effect. These properties warrant the study of VPA as a possible active treatment in people with severe COVID-19. Material and Methods. Consecutive adult patients needing invasive mechanical ventilation (IMV) will be given intravenous (IV) VPA at a starting dose of 20 mg/kg/day and up to 60/kg/day (in 60 min IV infusions in 250 mL normal saline) as needed to reach plasma VPA concentrations of 50-100 μg/mL (measured every 72 h). These patients will be followed-up for 10 days for the primary outcome and for a further period of 30 days after treatment completion for the secondary outcome of recurrence. The primary study outcome is the reduction in the case fatality rate (CFR) of at least 50 % after 10 days of treatment (as compared with natural history). Secondary outcomes are the reduction of length of stay (LOS) of at least 50 %, as well as COVID-19 recurrence at 30-day follow-up. The most important safety outcomes are acute liver failure, acute pancreatitis, and thrombocytopenia. Conclusions. Although long-term adverse effects and even pro-inflammatory consequences have been reported with the chronic use of VPA, the study of VPA is justified from a scientific standpoint given the urgent need for a drug against COVID-19 to shorten the high mortality and LOS.

Thrombocytopenia during intravenous valproic acid therapy in the neurological intensive care unit.

Thrombocytopenia is a common laboratory abnormality among critically ill patients under neurological intensive care unit (NCU) care. Valproic acid (VPA), a widely used antiepileptic drug, is one of the common causes of drug-induced thrombocytopenia. The purpose of this study was to estimate the incidence and risk factors of thrombocytopenia after intravenous VPA therapy among the patients admitted to NCU. We retrospectively reviewed the medical records of patients who were treated with intravenous VPA during their NCU stay between January 2014 and December 2018. We studied the frequency of thrombocytopenia and further evaluated the risk of thrombocytopenia in these patients. Among the 283 patients (181 male [64.0%], mean age: [61.0±14.9] years) who were treated with intravenous VPA, thrombocytopenia was observed in 104 patients (36.7%). Thrombocytopenia was associated with several risk factors, including lower baseline platelet counts (<200×109 /L); aetiologies other than intracranial or subarachnoid haemorrhage; longer use of VPA (more than 3days); higher daily dose of VPA (more than 1000mg/d); concurrent use of VPA with other antiepileptic drugs; infection; and the use of mechanical ventilation. Multivariate analysis found several independent risk factors of thrombocytopenia with intravenous VPA therapy, including lower baseline platelet counts, aetiologies other than intracranial or subarachnoid haemorrhage, use of VPA for more than 3days and infection. Thrombocytopenia is common in NCU patients. Because several clinical and laboratory factors are associated with thrombocytopenia, careful use of VPA should be considered in patients with these risk factors.

Abstract 272: Dose Optimization of Early High-Dose Valproic Acid for Neuroprotection After Cardiac Arrest

Introduction: High-dose valproic acid (VPA) has been shown to improve the survival and neurologic outcomes in preclinical brain injury models including asphyxial cardiac arrest (CA) in rats. However, its pharmacokinetics, pharmacodynamics, and safety profiles in large animal CA models are unknown. Hypothesis: High-dose VPA can be safely administered after return of spontaneous circulation (ROSC) and cross the blood-brain barrier dose-dependently in a swine CA model. Methods: After 8 minutes of untreated ventricular fibrillation CA, male Yorkshire swine [43.3 (3.0) kg] were resuscitated for up to 16 minutes until ROSC. They were randomized to receive placebo, 75 mg/kg, 150 mg/kg, or 300 mg/kg VPA as 90-minute intravenous infusion (n=5 per group) beginning 20 minutes after sustained ROSC. Animals were monitored for 2 additional hours after infusion ended and then euthanized. Experimental operators were blinded to the treatments. Results: The mean total cardiac arrest duration was 15.0 (1.6) minutes, with no significant differences between groups. At end of infusion, the serum free VPA concentration increased dose dependently, from 139.2 (10.1) mcg/mL [75 mg/kg VPA] to 287.2 (24.6) mcg/mL [150 mg/kg VPA] to 565.6 (36.5) mcg/mL [300 mg/kg VPA] (p&lt;0.05). This corresponded to a dose-dependent decrease in the fraction of serum protein-bound VPA, from 41.8% (1.8) [75 mg/kg VPA] to 23.4% (3.8) [150 mg/kg VPA] to 14.4% (3.8) [300 mg/kg VPA] (p&lt;0.05). Brain total VPA concentrations at end of experiment were 26.1 (3.1) mcg/g [75 mg/kg VPA], 72.5 (18.9) mcg/g [150 mg/kg VPA], and 212.3 (33.4) mcg/g [300 mg/kg VPA] (p&lt;0.05). There was a strong linear correlation between serum free VPA and brain total VPA concentrations (R 2 =0.98). All animals survived until euthanasia, although the 300 mg/kg group required more epinephrine to maintain mean arterial pressure greater than or equal to 80 mmHg and had higher lactic acidosis. Conclusion: Brain VPA concentrations correlate strongly with serum free VPA when high-dose intravenous VPA is given after ROSC in a swine CA model. These results provide the foundation for dose-optimization studies of high-dose VPA as a neuroprotective therapy following resuscitation from CA.

The use of intravenous valproic acid in patients with epileptic seizures developing during radiation therapy following glial tumor surgery

Objective: to study the effect of valproic acid on epileptic seizures developing during radiation therapy (RT) following glioma surgery in patients taking antiepileptic drugs (AED).Materials and methods. This prospective observational study involved 879 patients aged 18-78 with glioblastomas (GM) who were receiving RT. The patients underwent clinical and neurological examination, electroencephalography (EEG), and neuroimaging tests. After the examination and surgical treatment, patients were prescribed RT. During an RT procedure, the patient has to stay in a steady non-moving position for 30 min. To prevent the patient from developing sporadic or serial seizures during RT, we used valproic acid administered via the intravenous route. The efficacy and safety of valproic acid were evaluated together with the outcomes of RT.Results. Of 879 participants, symptomatic epilepsy was detected in 147 patients (16.7%). An increase in epileptic seizures (even under basic AED therapy) after surgery for GM was noted on days14-21 after the start of RT (i.e. between the 7 and 11th RT session) in 65 of 147 patients (44.2%). The iv administration of valproic acid allowed all 65 patients to complete the course of RT. No adverse events associated with the use of valproic acid were reported.Conclusion. This observation from our clinical practice allows us to recommend valproic acid for the treatment of epileptic seizures (focal and generalized) developing during radiotherapy after surgery for GM. The treatment should be accompanied by clinical, neurological and EEG monitoring.

Intravenous use of valproic acid in status epilepticus is associated with high risk of hyperammonemia

PurposeThe aim of the study was to examine the frequency of hyperammonemia secondary to valproic acid treatment in status epilepticus and to describe the characteristics of the patients. MethodsAll patients with established status epilepticus during 2014 to 2016 at Ryhov County Hospital were identified in a retrospective case series. Clinical and laboratory findings were collected from electronic medical files and the Metavision database at the intensive care unit (ICU). Hyperammonemia was defined as a concentration of at least 50 μmol/L. Results11 of 40 patients developed hyperammonemia. These patients had a significantly longer stay at the ICU (12.6 vs 2.5 days) and at the hospital (22 vs 11 days). All patients with hyperammonemia were treated at the ICU and all received antibiotics. 12 patients were treated with intravenous valproic acid outside the ICU. Hyperammonemia was not related to Body Mass Index, time to initiation of therapy or laboratory abnormalities except anemia (Hemoglobin 104 vs 122 g/l). There was no difference in mortality between groups. ConclusionThe risk of hyperammonemia is almost 40% in patients receiving intravenous valproic acid in the ICU setting. The underlying mechanisms are probably either individual susceptibility or high metabolic demands. A high vigilance should be recommended. These data require further research via prospective designs in which multiple variables are controlled to explore the effects of individual factors on treatment outcome.

F20. Focal status epilepticus in a patient with stroke like migraine attacks after radiation therapy (SMART) syndrome

Stroke like migraine attacks after radiation therapy (SMART) syndrome is a rare and under-recognized delayed complication of brain irradiation. It is characterized by cortical thickening with associated cortical gadolinium enhancement on magnetic resonance imaging (MRI) and with migraine headaches, typically reversible stroke like symptoms and focal seizures. Focal status epilepticus (SE) is a rare phenomenon associated with SMART syndrome. We present a case of SMART syndrome with focal seizures and SE. We also reviewed the literature on SMART and SE. A 46 year old male with history of human immunodeficiency virus, hypertension, diabetes mellitus II, brain lymphoma (treated with brain irradiation) presented with a two week history of right parietal headache with involuntary left leg movement and left hemi-neglect on exam. MRI showed evidence of cortical and subcortical T2/FLAIR hyperintensity with cortical and leptomeningeal enhancement involving the right parietal region. Serum paraneoplastic and infectious workup was negative. Cerebrospinal fluid (CSF) analysis was remarkable for albuminocytologic dissociation. CSF cytology was negative for malignancy. Electroencephalogram (EEG) sowed slowing over the right parasagittal area without evidence of epileptiform activity. Symptom resolution was achieved with intravenous valproic acid 500 mg twice daily (BID). He remained asymptomatic until readmission 9 months later for a 2 week history of right parietal headache along with altered sensory perception of the left arm and leg in space and left sensory extinction. CSF analysis and brain MRI findings were unchanged. Brain biopsy was negative for malignancy. EEG showed multiple electrographic seizures in the right posterior region. The SE was treated with brivaracetam 100 mg BID, valproic acid 500 mg BID and vigabatrin 1500 mg BID and later with topamax 200 mg BID, levetiracetam 1500 mg BID and lacosamide 100 mg BID. Seizure freedom was achieved at 3 weeks. Patient was discharged home on levetiracetam 500 mg BID and lacosamide 100 mg BID. Patient was readmitted a week later for agitation prompting discontinuation of both medications with initiation of eslicarbazepine 1200 mg daily was initiated with no recurrence of symptoms or side effects. At a 4 week follow up he remained asymptomatic. We reviewed the literature and identified five previously reported cases of SE associated with SMART syndrome. Seizures are not uncommon in patients with SMART syndrome likely secondary to underlying cortical irritability. Focal SE is rare and can be seen with SMART syndrome. Our report emphasizes the need to recognize SMART syndrome in a patient with headache and focal SE with a history of brain irradiation.

Valproic acid induces prosurvival transcriptomic changes in swine subjected to traumatic injury and hemorrhagic shock.

Valproic acid (VPA) is a histone deacetylase inhibitor that improves outcomes in large animal models of trauma. However, its protective mechanism of action is not completely understood. We sought to characterize the genetic changes induced by VPA treatment following traumatic injuries. Six female Yorkshire swine were subjected to traumatic brain injury (controlled cortical impact), polytrauma (liver and splenic laceration, rib fracture, rectus crush), and hemorrhagic shock (HS, 40% total blood volume). Following 2 hours of HS, animals were randomized to resuscitation with normal saline (NS) or NS + 150 mg/kg of intravenous VPA (n = 3/cohort, 18 samples total). Blood samples were collected for isolation of peripheral blood mononuclear cells at three distinct time points: baseline, 6 hours following injuries, and on postinjury day 1. RNA was extracted from peripheral blood mononuclear cells and sequenced. Differential expression analysis (false discovery rate < 0.001 and p value <0.001) and gene set enrichment (Panther Gene Ontology and Ingenuity Pathway Analysis) was used to compare VPA to non-VPA-treated animals. A total of 628 differentially expressed RNA transcripts were identified, 412 of which were used for analysis. There was no difference between treatment groups at baseline. The VPA-induced genetic changes were similar at 6 hours and on postinjury day 1. Upregulated genes were associated with gene expression (p 2.13E-34), cellular development (1.19E-33), cellular growth and proliferation (1.25E-30), and glucocorticoid receptor signaling (8.6E-21). Downregulated genes were associated with cell cycle checkpoint regulation (3.64E-22), apoptosis signaling (6.54E-21), acute phase response signaling (5.84E-23), and the inflammasome pathway (1.7E-19). In injured swine, VPA increases the expression of genes associated with cell survival, proliferation, and differentiation and decreases those associated with cell death and inflammation. These genetic changes could explain the superior clinical outcomes in VPA-treated animals, including smaller brain lesion size and improved neurologic recovery.

Intravenous Valproic Acid Add-On Therapy in Acute Agitation Adolescents With Suspected Substance Abuse: A Report of Six Cases.

The aim of this study was to test efficacy and safety of intravenous (IV) valproate for aggression in children and adolescents with mood or conduct disorder and concomitant substance abuse. Six patients received a 20 mg/kg dose of IV valproic acid as an add-on therapy to their standard therapy with second-generation antipsychotics and benzodiazepines. Agitation and general psychopathology were measured at baseline and after the first injection using the Modified Overt Aggression Scale, the Brief Psychiatric Rating Scale, and the Children's Global Assessment Scale. The findings suggested that in emergency psychiatry clinical settings, IV valproate was effective in reducing agitation and aggressive behaviors with a good tolerability profile and better treatment compliance.

Resting-state functional connectivity changes due to acute and short-term valproic acid administration in the baboon model of GGE

Resting-state functional connectivity (FC) is altered in baboons with genetic generalized epilepsy (GGE) compared to healthy controls (CTL). We compared FC changes between GGE and CTL groups after intravenous injection of valproic acid (VPA) and following one-week of orally administered VPA. Seven epileptic (2 females) and six CTL (3 females) baboons underwent resting-state fMRI (rs-fMRI) at 1) baseline, 2) after intravenous acute VPA administration (20 mg/kg), and 3) following seven-day oral, subacute VPA therapy (20–80 mg/kg/day). FC was evaluated using a data-driven approach, while regressing out the group-wise effects of age, gender and VPA levels. Sixteen networks were identified by independent component analysis (ICA). Each network mask was thresholded (z > 4.00; p < 0.001), and used to compare group-wise FC differences between baseline, intravenous and oral VPA treatment states between GGE and CTL groups. At baseline, FC was increased in most cortical networks of the GGE group but decreased in the thalamic network. After intravenous acute VPA, FC increased in the basal ganglia network and decreased in the parietal network of epileptic baboons to presumed nodes associated with the epileptic network. After oral VPA therapy, FC was decreased in GGE baboons only the orbitofrontal networks connections to the primary somatosensory cortices, reflecting a reversal from baseline comparisons. VPA therapy affects FC in the baboon model of GGE after a single intravenous dose—possibly by facilitating subcortical modulation of the epileptic network and suppressing seizure generation—and after short-term oral VPA treatment, reversing the abnormal baseline increases in FC in the orbitofrontal network. While there is a need to correlate these FC changes with simultaneous EEG recording and seizure outcomes, this study demonstrates the feasibility of evaluating rs-fMRI effects of antiepileptic medications even after short-term exposure.